Neuraxial hydrophilic opioid is the gold standard for postcesarean delivery analgesia.1 However, this may result in adverse effects (itching, nausea, vomiting, urinary retention, and early or late respiratory depression), and the use of adjuvant drugs could be beneficial.2 Clonidine, an α-2 adrenergic agonist, stimulates receptors in the posterior cords of the spinal medulla, modulating painful ascending pathways,3 and effectively controlling both visceral and somatic pain.1 It has been used as an intrathecal adjuvant, and its effects have been assessed by many studies for cesarean delivery: analgesic potential, improved intraoperative analgesia quality, and less pain sensitization.4–10
Systemic clonidine (oral or intravenous [IV]) has been used as a preanesthetic drug for attenuation of perioperative hemodynamic instability, for reducing anesthetic needs during surgery, and for reducing postoperative analgesic requirements.3,11–17 Oral clonidine reduced the postoperative morphine requirements.18 No studies have evaluated IV clonidine as adjuvant for cesarean delivery anesthesia.
The aim of this study was to evaluate postoperative pain after cesarean delivery among 3 types of anesthesia: standard spinal anesthesia, standard spinal anesthesia combined with intrathecal clonidine, and standard spinal anesthesia combined with IV clonidine.
This article adheres to the applicable Enhancing the Quality and Transparency of Health Research checklist. The research was approved by the Clinics Hospital of University of São Paulo Ethics in Research Committee (CAAE 05847312.8.0000.0068, No: 940.941). Before patient enrollment, the trial was registered at clinicaltrials.gov (NCT02550444, principal investigator: H.S.F.; date of registration: April 2015). Written informed consent was obtained from all subjects participating in the trial. The patients were recruited from April 2015 to April 2016.
Inclusion criteria were parturients with American Society of Anesthesiology physical status II, age 18 years or older, term singleton pregnancy, undergoing elective cesarean delivery, with a Pfannenstiel incision, under spinal anesthesia. The exclusion criteria were parturient in the presence of labor, contraindications for neuraxial anesthesia; contraindications for any of the drugs involved in the study; uncontrolled high blood pressure or diabetes mellitus in need of insulin therapy; IV psychotropic drug use; previously known malformations of the fetus; and patients with a previous history of chronic pain.
Patients were randomized to one of 3 groups using a computer-generated random numbers table. The drugs were stored inside a sealed box, previously prepared by hospital’s research pharmacy, according to the randomization, with no identification. The professional who administered the drugs was external to the research group and was blind to the intervention administered. The researcher who analyzed the data was also blind to which intervention had been performed. In the control group, patients received IV and intrathecal placebo (0.9% sodium chloride [NaCl]). In the intrathecal clonidine group, patients received 75 µg of spinal clonidine and IV placebo. In the IV clonidine group, patients received 75 µg of IV clonidine and spinal placebo. The solution volumes were standardized across groups by the addition of 0.9% NaCl.
All subjects were managed according to the hospital protocol for cesarean delivery, and the only difference among groups was the clonidine or placebo given intrathecally or IV. Multiparameter monitoring (pulse oximetry, electrocardiogram monitor, noninvasive blood pressure measures) was used. The patients received an IV Ringer’s lactate 10 mL/kg bolus during spinal anesthesia with 0.5% hyperbaric bupivacaine (15 mg), 0.02% morphine (80 µg), 0.005% fentanyl (10 µg), and clonidine 0.015% (75 µg) or placebo (0.5 mL of 0.9% NaCl), mixed into the intrathecal dose, in a solution with total volume of 4.1 mL. Blood pressure was measured noninvasively during the intraoperative period, every minute until the baby was born, and every 3 minutes after delivery. Low blood pressure (decrease of 10% of base values) was treated with IV metaraminol 0.2 mg bolus and/or IV ephedrine 5 mg bolus. Bradycardia was defined as heart rate (HR) <45 bpm and was treated with IV atropine 0.5 mg bolus. Intraoperative rescue analgesia was provided, if necessary, according to the patient’s need or when the anesthetist found it necessary, with IV fentanyl bolus, until a maximum dose of 100 µg. If this dose was not enough, the anesthetist could conduct the case as desired, (supplemental ketamine, general anesthesia) and the patient was excluded from the study. Before the skin incision, the patient received 2 g IV cefazolin. After umbilical cord clamping, patients received IV oxytocin 5–10 IU diluted in Ringer’s lactate 250 mL, ketoprofen 100 mg IV, dipyrone 2 g IV, omeprazole 40 mg IV, and ondansetron 8 mg IV. After the procedure, women were transferred to the postanesthetic care unit (PACU). There, they could receive morphine 2 mg IV, every 5 minutes, as needed for pain. Postoperative pain control in the ward was standardized according to the following protocol: scheduled ketoprofen 100 mg IV twice per day, scheduled dipyrone 2 g IV 4 times per day, tramadol IV 100 mg as needed, maximum 3 times per day in the case of uncontrolled pain. If pain persisted, morphine subcutaneously 5 mg was administered by nursing staff, every 4 hours. Nausea was treated with dimenhydrinate 50 mg IV 4 times per day and metoclopramide 10 mg IV 3 times per day, and itch was attenuated with diphenhydramine 25 mg IV.
A neonatology team was present for every delivery and was responsible for the first evaluation of the neonate, including Apgar score and resuscitation.
Primary outcome was acute postoperative pain intensity at movement 6, 12, 24, and 48 hours after the induction of spinal anesthesia. Secondary outcomes were opioid requirements, neonatal Apgar scores, blood gas results, adverse effects, and chronic postoperative pain (after 3 months).
Data including age, height, weight, body mass index, number of pregnancies, number of deliveries, American Society of Anesthesiology physical status classification, duration of anesthesia, amount of fluid needed, basal blood pressure, minimum and maximum values, HR variation, vasopressor and chronotropic drug needs, adverse effects (sedation, nausea, vomiting, itching, and shivering), and intraoperative analgesic complementation were registered. Low blood pressure was considered when systolic blood pressure values decreased >20% of baseline values.
Immediately after the delivery of the neonate, 1.6 mL of umbilical artery blood was collected from the umbilical cord, between 2 clamps, and sent for immediate analysis. The neonate outcomes collected included gestational age; birth weight; Apgar score at 1, 5, and 10 minutes; umbilical artery blood gas analysis; and the need for admission to the neonatal intensive care unit.
During the stay in the PACU, motor block was assessed every 10 minutes. It was considered present if the patient was not able to perform a 90° flexion movement of the thighs over the hips and a 90° extension movement of the legs over the thighs, on both inferior limbs, simultaneously and sustained for at least 5 seconds. Pain and adverse effects were also evaluated. Patients were assessed by researchers at PACU arrival and at 6, 12, 24, and 48 hours after the induction of spinal anesthesia. Postoperative pain was assessed using the Numerical Verbal Scale, from 0 to 10 (0 is equivalent to no pain at all and 10 to the worst pain ever experienced). Patients described their pain at rest and after being asked to change from lying position to sitting position. Treatment satisfaction was evaluated using a 0–10 scale, in which 0 meant unsatisfied and 10 meant fully satisfied. Patients were asked by the research team to quantify the intensity of itching, nausea, vomiting, and dizziness on a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). Sedation was measured using the Richmond Agitation and Sedation Scale.19 Tramadol, morphine, dimenhydrinate, metoclopramide, and diphenhydramine needs during the hospital stay were also registered.
After 3 months, women were evaluated by telephone interview, when they were asked if they had any pain or abnormal sensation (burning, itching, and numbness) at the incision site, how intense those symptoms were (from 0 to 10), if they had any functional limitation due to pain, and if they needed any drugs for surgical site pain during the week before the interview.
SPSS 13.0 (SPSS, Inc, Chicago, IL) was used for statistical analyses. The data are presented as means ± standard deviation or as percentages. To estimate differences in normally distributed continuous outcome variables, analysis of variance (ANOVA) was used with Bonferroni or Dunn corrections. Kruskal–Wallis and χ2 tests were used for the noncontinuous variables. For early postoperative pain evolution assessment among the groups, repeated measures ANOVA test was used with group-by-time interaction. Statistical significance was defined as a P value <.05.
Sample size was calculated using published data on intrathecal clonidine early analgesic effects (intrathecal clonidine versus control).8 Using power of 80% and an α of .05 for a pain Numerical Verbal Scale difference of at least 2 points between clonidine groups and control, with standard deviation of 2, 16 patients would be needed for each trial arm.20 To account for possible loss to follow-up, it was decided to include 26 patients per trial arm.
A total of 78 women were initially enrolled, but 14 were excluded: 1 had a major bleeding complication requiring general anesthesia; 1 had severe psychomotor agitation during the cesarean delivery, requiring use of drugs that had not been included in the protocol (haloperidol); 2 had neonates with severe malformations that were not previously known; and 10 were submitted to other anesthesia techniques. Among the 64 included patients, 59 participated in the evaluation at 3 months postpartum. We were not able to make telephone contact with the other 5 patients. Randomization resulted in 20 patients for the control group, 22 for the intrathecal clonidine group, and 22 for the IV clonidine group (Figure 1).
Patient characteristics are summarized in Table 1. There were no clinically important differences among the groups for demographic characteristics or preoperative variables.
There were no differences among groups for postcesarean delivery pain at rest and at movement (repeated measures ANOVA: group-by-time interaction P values of .57 [at rest] and .85 [at movement]) (Figure 2). There were no differences among groups for pain at movement at 24-hour postcesarean moment: 4.53 ± 3.0 vs 4.45 ± 2.73 vs 3.93 ± 3.07 for control, intrathecal, and IV, respectively, ANOVA P = .771 (Table 2).
There were no differences for tramadol (opioid) consumption (Kruskal–Wallis test, P = .825). No patient needed morphine at any time.
There were no differences among the groups for intraoperative hemodynamic variables. The clonidine groups showed higher sedation levels compared to the control group (Table 3).
The neonatal blood gas analyses are summarized in Table 4. There were no differences among the groups, after Bonferroni corrections, for umbilical artery blood gas analyses. We had no differences among groups for Apgar scores.
The 3-month postoperative telephone interview showed that 22% of the patients had chronic pain at that time, with no differences among the groups. Analgesic drug was not different among the 3 groups after Bonferroni corrections (P = .073 for intrathecal versus control; P > .999 for IV versus control; and P = .181 for intrathecal versus IV).
This study showed that intrathecal and IV clonidine, when used as an adjuvant to spinal anesthesia for elective cesarean delivery, caused higher levels of intraoperative sedation but offered no benefits for postoperative analgesia. There were no differences among groups for postoperative adverse effects or neonate outcomes.
Intrathecal clonidine is used in anesthesia, including obstetric anesthesia as an adjuvant for cesarean delivery requiring spinal and epidural block.2 Kothari et al9 compared different doses of bupivacaine to intrathecal clonidine in the context of cesarean delivery. They concluded that clonidine increases acute analgesia and showed a local anesthetic sparing effect. The group that received the highest bupivacaine dose (12.5 mg) exhibited more bradycardia than did the groups that received clonidine. Clonidine caused more sedation.9 Neves et al7 showed that the minimum effective dose for the analgesic effect of intrathecal clonidine was 15 µg (improved postoperative analgesia, with no maternal or neonatal side effects). Van Tuijl et al8 used 75 µg clonidine and demonstrated longer postoperative analgesia, with no difference in opioid consumption. There were no side effects or neonatal repercussions, including factors investigated through umbilical artery blood gas analyses. Paech et al6 used different intrathecal clonidine doses in association with intrathecal morphine 100 µg. Clonidine doses ranging from 60 to 150 µg led to prolonged analgesia and lower opioid need. Patients presented more sedation but no differences in hemodynamic parameters or neonatal Apgar scores.6 Our findings are partly in accordance with those of previous studies. We had no evidence of early or late postoperative analgesic benefits, but we also found higher sedation levels in patients receiving the drug (intrathecal or IV).
Pain scores did not differ among the groups in our study. One reason might be that we had a very robust anesthetic and analgesic protocol in all groups, including intrathecal bupivacaine, morphine and fentanyl, IV dipyrone and ketoprofen, IV tramadol, and subcutaneous morphine as needed for noncontrolled pain. Multimodal analgesia is widely used for postoperative pain management, and the use of adjuvants such as clonidine might be used as part of the multimodal protocol. However, our results did not show any improvement in pain management with the different routes of clonidine, in a multimodal analgesia regimen with spinal opioid, nonsteroidal anti-inflammatory drugs, nonopioid analgesic, and rescue opioid. Most previous studies that showed more robust differences included only local anesthetic, with or without clonidine.
In our study, chronic pain was present in 22% of the patients 3 months postoperatively, with no differences among the groups. There were no differences in pain scores or functional capacity between groups at 3 months. In 2008, a study reported antihyperalgesic and analgesic effects of 150 µg of intrathecal clonidine 48 hours after elective cesarean delivery.10 They also assessed the clonidine effect in chronic postcesarean delivery pain but found no differences in pain incidence, pain intensity, and analgesics intake at 1, 3, and 6 months after surgery. However, this work was initially designed to evaluate early postoperative analgesic effects. So, this study does not have statistical power to evaluate chronic postcesarean delivery pain as a primary outcome.
One report that investigated different adjuvant drugs in spinal anesthesia for cesarean delivery demonstrated that clonidine increased motor block duration, caused more sedation, and prolonged low blood pressure.21 We found no significant decrease in blood pressure levels in the clonidine groups.
Systemic α-2 agonists are commonly used in anesthesia practice, sometimes as oral premedication. Sedation, hypnosis, and other anxiolytic, sympatholytic, and analgesic effects of clonidine are useful in the perioperative period.22,23 Clonidine reduces opioid consumption, intraoperative and postoperative pain scores, and postoperative nausea. However, it may cause more intraoperative and postoperative hypotension.17,24 Although some studies have been published using IV clonidine for nonobstetric patients, there are no such reports on obstetric anesthesia. One study, in 2001, evaluated the effects of systemic clonidine in obstetrics (oral preanesthetic drug, 4 µg/kg, 1 hour before cesarean delivery). The authors showed no differences in hemodynamics outcomes, pain scores, or sedation, but morphine consumption was reduced in the first 48 hours postoperatively. There were no neonatal repercussions (Apgar scores, neonatal HR, umbilical artery blood gas analyses).18 In our study, the IV clonidine group showed no differences in hemodynamics, analgesics consumption, neonatal outcomes, or side effects, except for sedation, in comparison to the placebo group.
This was the first study using IV clonidine for cesarean delivery anesthesia, and it brings a new discussion on the role of clonidine through different routes in postoperative pain. We found no significant role of spinal or IV clonidine in pain scores. This result may lead to the reevaluation of clonidine use in obstetrics analgesia after cesarean delivery.
One limitation of this trial is the IV clonidine dose used. In most studies, IV and oral clonidine were used in higher doses than those used here. We used 75 µg because one of the aims of the study was to evaluate possible consequences of different drug administration routes, and we desired to limit sedation. Nevertheless, both groups experienced sedation at this dose.
In conclusion, neither intrathecal nor IV clonidine improved postcesarean pain. They caused more sedation in patients submitted to cesarean delivery under spinal anesthesia, with no other adverse effects or neonate repercussions, in comparison with placebo.
The authors thank the Obstetrical Department and colleagues of the Obstetrical Anesthesia team at the Hospital das Clínicas.
Name: Hermann S. Fernandes, MD.
Contribution: This author helped design the study, recruit the patients, collect the data, and write the manuscript.
Name: Fernando Bliacheriene, PhD.
Contribution: This author helped design the study, analyze the data, recruit the patients, and write the manuscript.
Name: Thúlio M. Vago, MD.
Contribution: This author helped recruit the patients and collect the data.
Name: Gabriela T. Corregliano, MD.
Contribution: This author helped recruit the patients.
Name: Marcelo L. Torres, PhD.
Contribution: This author helped analyze the data.
Name: Rossana P. Francisco, PhD.
Contribution: This author helped design the study.
Name: Hazem A. Ashmawi, PhD.
Contribution: This author collaborated on writing the manuscript.
This manuscript was handled by: Jill M. Mhyre, MD.
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